Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related deaths worldwide. HCC is a type of malignancy whose pathogenesis is induced by a combination of genetic and environmental factors. Among the environmental factors, HBV or HCV infections are the major risk factors. Recent molecular and genetic studies have demonstrated that HBV and HCV viral proteins have direct roles during HCC pathogenesis by de-regulating signaling pathways important for hepatocyte proliferation, differentiation and apoptosis.15 However, the long latency and low incidence rate of HCC development from the HBV or HCV transgenic mice studies suggest that additional genetic mutations occur in these damaged hepatocytes, which are required for the malignant transformation and HCC formation. The goal of the proposal is to characterize the virus-gene interactions during hepatic carcinogenesis. We hypothesize that specific genetic events, such as c-Myc or c-Met overexpression, -catenin activating mutations, and loss of tumor suppressor genes TP53, will accelerate HCC development in HBV or HCV core transgenic mice. To test the hypothesis, we propose two Specific Aims. In Aim One, we will determine the genetic alteration(s) that induces hepatic carcinogenesis in HBV transgenic mice; and in Aim Two, we will determine the genetic alteration(s) that induces hepatic carcinogenesis in HCV Core transgenic mice. To achieve these aims, we will apply hydrodynamic transfection method to directly target genes (using either expression vectors or shRNA constructs) into mouse hepatocytes for long term and stable expression. The genes that we plan to express into HBV or HCV core transgenic mice include: c-Myc, c-Met, N90-2-catenin and sh-p53, all representing common genetic modifications observed during human HCC pathogenesis. By expressing these specific genes into the mouse liver, we will determine whether any of these genetic alterations is able to accelerate HCC development when mice are predisposed to hepatic carcinogenesis induced by HBV entire genome or HCV core protein expression. Altogether, the proposed studies will be of great help in identifying important driver oncogenes or tumor suppressor genes that have critical roles during liver cancer pathogenesis. The study will also provide novel insight into the molecular mechanisms of HCC development in the context of viral oncoprotein expression. The murine models generated from the proposed study will significantly benefit HCC research community and provide valuable in vivo models to study novel strategies for HCC prevention and treatment.